Tetraamides and method for improving feed utilization

ABSTRACT

Disclosed are novel tetraamide compounds and intermediates therefor which are useful in methods for improving feed conversion and/or weight gain in animals such as chickens.

FIELD OF INVENTION

The present invention relates to novel compounds and methods forimproving feed conversion and/or weight gain in animals.

BACKGROUND OF THE INVENTION

As is well known, there is a need to develop methods that increase oroptimize the productivity of animals to enhance food production. Notonly does the producer benefit by lower costs of production but theconsumer benefits ultimately from increased supplies of meat and animalproducts at a lower cost.

For approximately the last 35 years, antibiotics such as penicillin, thetetracyclines, and bacitracin have enabled benefits to both producer andconsumer by enhancing growth and/or improving feed conversion inanimals, most effectively in poultry and swine.

Benefits from incorporating antibiotics into animal feeds are usuallyattributed to their minimizing the deleterious effects of pathogenicmicroorganisms in the gastrointestinal tract of the host. Evidence forthe induction of antibiotic-resistant microorganisms and concern fortheir possible transfer to and infection of humans have generated broadsearches for compounds that will improve animal performance withoutsubstantially impinging on human health concerns.

SUMMARY OF THE INVENTION

We have now discovered certain tetraamides as hereinafter describedwhich have beneficial effects on improving animal performance.

More specifically, the present invention is directed to a method forincreasing the efficiency of feed utilization by animals which comprisesadministering the said animals an effective feed utilization efficiencyincreasing amount of a tetraamide compound of the formula ##STR1##wherein each R is, independently, an alkyl group of 1 to 6 carbon atoms;and each R¹ is, independently, an alkyl group of 1 to 6 carbons orhydrogen.

The present invention is also directed to the novel compounds of FormulaI.

The present invention also includes certain intermediate compounds usedto prepare the compounds of Formula I. Such intermediates are of theformula: ##STR2## wherein each R and R¹ are, independently, as describedabove.

The present invention is also directed to a method for promoting thegrowth of meat-producing animals comprising administering an effectivegrowth promoting amount of a compound of Formula I to meat-producinganimals.

The present invention is also directed to an animal feed compositioncomprising standard animal feed in admixture with from about 20 partsper million (ppm) to about 1,000 ppm of the total amount of the ultimatediet formulation of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "animals" excludes humans and refers to anyanimal grown in the art of animal husbandry for use by humans for food,clothing and the like; such animals include meat-producing,egg-producing, and milk-producing animals; for example, ruminants suchas cattle, sheep and goats and nonruminants such as swine and poultry.The term "meat-producing animals" refers to any animal grown in the artof animal husbandry for use of its meat as food. The term"egg-producing" animals refers to any animal grown in the art of animalhusbandry for use of its eggs as food. The term "milk-producing animal"refers to any animal grown in the art for use of its milk as food. Theterm "standard animal feed" refers to that feed that can be used in theanimal husbandry field and is suitable to be fed to animals to supplypart or all of the animals' nutrient requirements. The term "effectivefeed utilization efficiency increasing amount" refers to that amount ofa compound of Formula I that, when administered to animals, willincrease the feed utilization efficiency of such animals, without anysignificant adverse side effect, as compared to untreated animals. It iscontemplated that such amount of Compound I will also result in otherbeneficial effects as a result of the increased feed conversionefficiency such as increased efficiency of egg production, milkproduction, wool production, and the like. The term "effective growthpromoting amount" refers to that amount of a compound of Formula I thatwill, when administered to meat-producing animals, promote the growthof, increase the growth rate of, and/or increase the weight gain of suchmeat-producing animals, without any significant adverse side effect, ascompared to untreated animals.

It is to be understood that the methods for feed utilization efficiencyimprovement and growth promotion will in many circumstances overlap.However, the two types of methods are recognized in the art as beingdifferent in many instances. As a result, for example, some treatedanimals may demonstrate increased feed conversion efficiency withoutconcommitant growth promotion. This may be desired in some situations,for example, in poultry such as chickens wherein the primary purpose forgrowing the chickens is for egg production. A typical effective feedutilization efficiency increasing amount of a compound of Formula I isabout 2 to about 100 milligrams (mg) per kilogram (kg) of body weightper day; a more preferred range is about 5 to about 50 mg per kg of bodyweight per day. Typical effective growth promoting amounts of thecompound of Formula I are about the same as the effective feedutilization efficiency increasing amounts.

As appreciated in the art, effective amounts of a compound of Formula Ifor use in the present invention will vary somewhat depending upon theparticular species of animal, age, growth conditions such as temperatureand type of feed, and the like. For any particular case, the exact oroptimal effective amount to be administered can be determined byconventional dose titration techniques. Also, it is contemplated that amixture of two or more of the compounds of Formula I can be used in themethods of the present invention.

For either of the two methods of the present invention nonruminantanimals are preferred, especially poultry. Of the preferred poultry, themost preferred is chickens.

In the feed conversion efficiency improvement method of the presentinvention it is preferred that the feed conversion efficiency isimproved at least about 1.0%, more preferred is at least about 2.0%, ascompared to untreated animals. In the growth promotion method of thepresent invention it is preferred that treated animals have at leastabout a 2.0%, more preferred is at least about a 4.0%, increase inweight gain as compared to untreated animals.

The compositions of the present invention can be formulated as end usefeed mixes or can be formulated as feed premixes, supplements orconcentrates. The compositions of the present invention can optionallycontain one or more other physiologically acceptable additives which canbe inert or act as adjuvants. Such additives include, but are notlimited to, nutrients and carriers such as amino acids, organic acids,soybean meal, ground corn, ground corn cobs, corn oil, barley, wheat orother edible feed grade material, mineral or vitamin mixtures; innocuousdiluents such as an alcohol, a glycol, or molasses; feed preservatives;antibiotics; coccidiostats; and the like. The compound of Formula I,whether administered via water or feed, can be used in combination withother treatments, whether for the same or a different purpose, such asuse of drugs and hormone implants.

The form of administration of a compound of Formula I to the animal isnot crucial, and alternative forms for administering the tetraamidecompound may be employed. For instance, the compound can be incorporatedinto tablets, drenches, salt blocks, paste, boluses, or capsules anddoped to the animals. Formulation of the compounds in such dosage formscan be accomplished by means of methods well known in the veterinarypharmaceutical art. Each individual dosage unit should contain aquantity of the compound which has a direct relation to the proper dailydose for the animal to be treated, as discussed above.

The compositions of the present invention contain an amount of thecompound of Formula I in order for the animals to consume an amount ofsaid compound that will be effective in improving the animals feedconversion and/or promoting the growth of said animal. The compositionsof the present invention are diet formulations comprising standardanimal feed for meat-producing animals in admixture with from about 20ppm to about 1,000 ppm of the total amount of the ultimate dietformulation of the compound of Formula I; a preferred amount of saidcompound is from about 50 ppm to about 500 ppm; and a most preferredamount of said compound is from about 100 ppm to about 300 ppm. Orallyadministering compositions with the above noted concentration of thecompound of Formula I will result in the treated animals receiving aneffective amount of the compound of Formula I. Therefore a method fororally administering such compositions to animals is also within thescope of the present invention. The exact amount desired to be in thediet formulation will vary depending upon age, weight, health andspecies of animal, the specific compound of Formula I or mixture ofcompound of Formula I, other components in the diet formulation, and thelike.

In the compound of Formula I it is preferred that R is an alkyl group of3-5 carbons. It is most preferred that R is isobutyl. It is preferredthat R¹ is an alkyl group of 1-3 carbons. It is most preferred that R¹is ethyl. The compound of Formula I can be prepared by the routeoutlined in the scheme below. ##STR3##

This scheme shows how (I) can be prepared. The starting materials forthis scheme are either commercially available or can be prepared bytechniques well known in the art. A number of variations are possible,including choice of base, solvent and reaction conditions. Typical basesinclude, for example, triethylamine, diethylisopropylamine, and sodiumcarbonate; typical solvents include, for example, 1,2-dimethoxyethane,dimethylformamide, and dimethylsulfoxide; typical reaction conditionsinclude, for example, a temperature of 50° to 100° C. for a reactionperiod of 1 to 24 hours. It is also possible that the last two steps inthe above scheme can be combined into one operation. The chloroamideused in steps 2 and 3 can be prepared from the correspondingdisubstituted amine and chloroacetyl chloride in the presence of base.In addition, other haloamides such as the appropriate bromoamide oriodoamide can be used in place of the chloroamide in steps 2 and 3.

The salts of the compounds of this invention can be derived fromphysiologically acceptable acids. Such physiologically acceptable acidsinclude inorganic acids, e.g., hydrochloric acid, nitric acid,phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid,nitrous acid, phosphorous acid, and the like, as well as organic acids,such as aliphatic mono- or dicarboxylic acids, phenyl-substitutedalkanecarboxylic acids, hydroxyalkanecarboxylic acids oralkanedicarboxylic acids, aromatic acids, aliphatic or aromatic sulfonicacids, and the like.

Physiologically acceptable salts of these acids include therefore, forexample, the sulfate, pryosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride,acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propionate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate,beta-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, andthe like.

The salts of the compound of the present invention can be preparedaccording to procedures commonly employed for the preparation of aminesalts. For example, the free base form of a compound of Formula I isdissolved in a suitable solvent, and an aqueous or organic solution ofthe desired acid is added. The salts can be isolated by filtration andrecrystallization or by evaporation of the solvent and purification.

EXAMPLES

The following examples are provided in order to further illustrate thepresent invention and should not be construed as limiting the inventionin any way.

EXAMPLE I Preparation of Compound II wherein R¹ =Ethyl

Diol II (R¹ =ethyl) was prepared by a procedure similar to thatdescribed in the literature (H. Maeda et al., Bulletin of the ChemicalSociety of Japan, 56, 3073 (1983)). Sodium carbonate (8.0 g, 75.0 mmol),R-(-)2-amino-1-butanol (44.5 g, 50.0 mmol, 46.0 mL) and1,8-dichloro-3,6-dioxaoctane (9.35 g, 50.0 mmol, 7.8 mL) were combinedand heated to 120° C. for 24 hours. When the reaction mixture hadcooled, it was filtered. The filtrate was concentrated and distilledusing a Kugelrohr apparatus (0.05 mm, 175°-200° C.). The distilledmaterial contained about 5% starting material as indicated by gaschromatography. The viscous oil was triturated with ether/hexanes togive a waxy white solid. The yield was 8.9 g (61%). The NMR spectrum,infrared spectrum and field desorption mass spectrum (FDMS) confirmedthe structure of the desired product.

EXAMPLE II Preparation of Compound III wherein R=Isobutyl and R¹ =Ethyl

A mixture of Compound II (R¹ =ethyl), 2-chloro-N,N-diisobutylacetamide(2.05 g, 0.01 mol), triethylamine (1.3 mL) and dimethoxyethane (10 mL)was heated to reflux under an argon atmosphere. After 24 hours thereaction was shown to be incomplete. More dimethoxyethane (10 mL),chloroamide as described above (2.05 g) and triethylamine (1.3 mL) wereadded. The mixture was again heated to reflux. After 17 hours thesolvent was removed, and the residue was partitioned between methylenechloride and 1N HCl. The acidic layer was made basic and extracted withethyl acetate. The ethyl acetate layer was dried and concentrated to alight yellow oil (0.94 g). The NMR spectrum, infrared spectrum and themass spectrum (field desorption) of the yellow oil were consistent withthe desired structure.

EXAMPLE III Preparation of Compound I wherein R=Isobutyl, and R¹ =Ethyl

Diamidediol Compound III (R=isobutyl, R¹ =ethyl) (0.45 g, 0.0008 mol)was combined with 2-chloro-N,N-diisobutylacetamide (0.36 g, 0.0018 mol),sodium hydride (60% in mineral oil, 75 mg) and dimethoxyethane (10 mL)and heated to reflux for two hours. After the reaction mixture hadcooled, one drop of water was added, and the solvent was removed. Theresidue was partitioned between methylene chloride and 1N HCl. Theorganic layer was washed with aqueous sodium carbonate, and the solventwas evaporated to give 0.84 g of an oil. This crude material waschromatographed through alumina (neutral) with heptane and then ether.Because little alumina was used, the product eluted from the column inthe early fractions with heptane as the eluant. This material was shownto be >95% pure by NMR, infrared and mass spectrum.

EXAMPLE IV

Birds arriving before two days of age were given water and the untreatedcontrol diet ad libitum until they were two days old. Approximately 10%extra birds were ordered to enable discard of the runts and giants.Birds were distributed by weight as evenly as possible to provide fourpens of ten birds each on each treatment. Distribution of pens in thebrooders was random, but restricted to ensure at least one pen in theupper two tiers, at least one pen in the middle two tiers, and at leastone pen in the lower two tiers for each treatment. Brooder temperatureswere approximately 95° F. throughout the trial. The compounds of Formula(I) were dissolved in ethanol prior to premixing with the basal diet.Water and feed were provided ad libitum. Feed/gain calculations includeweight gained by birds dying during the second week of the experiment.The specific diets, other test conditions and results are shown inTables 1-4.

UNTREATED CONTROL DIET

                  TABLE 1                                                         ______________________________________                                        Composition of Semi-Purified Diet for Broiler Chicks                          Ingredient           Amount (%)                                               ______________________________________                                        Sucrose              62.55                                                    Isolated Soy Protein 26.90                                                    (Pro-Fam S-901).sup.a                                                         Salt Mixture (DCH SYN MIN).sup.b                                                                   4.35                                                     Refined Soybean Oil.sup.c                                                                          4.50                                                     Glycine              0.30                                                     Choline Chloride     0.20                                                     Inositol             0.10                                                     Vitamin Premix (DCH SYN VIT).sup.d                                                                 0.50                                                     dl-Methionine        0.60                                                                          100.00                                                   ______________________________________                                         .sup.a Grain Processing Corporation                                           .sup.b See Table 2                                                            .sup.c Crisco or equivalent                                                   .sup.d See Table 3                                                       

                  TABLE 2                                                         ______________________________________                                        Composition of Salt Mixture (DCH SYN MIN)                                     Ingredient                 gm                                                 ______________________________________                                        Calcium Carbonate (CaCO.sub.3)                                                                           1050.0                                             Potassium Phosphate, Dibasic (K.sub.2 HPO.sub.4)                                                         462.0                                              Sodium Phosphate, Dibasic (Na.sub.2 HPO.sub.4)                                                           330.0                                              Calcium Phosphate, Monobasic [Ca(H.sub.2 PO.sub.4).sub.2.H.sub.2 O]                                      500.0                                              Sodium Chloride (NaCl)     264.0                                              Magnesium Sulfate (MgSO.sub.4)                                                                           161.2                                              Manganous Sulfate (MnSO.sub.4.H.sub.2 O)                                                                 19.8                                               Potassium Iodide (KI)      0.07                                               Zinc Carbonate (ZnCO.sub.3)                                                                              6.6                                                Cupric Sulfate (CuSO.sub.4.5H.sub.2 O)                                                                   0.79                                               Ferric Citrate             10.56                                              Sodium Molybdate (Na.sub.2 MoO.sub.4.2H.sub.2 O)                                                         0.4                                                Sodium Selenite (Na.sub.2 SeO.sub.3)                                                                     0.073                                                                         2805.493                                           ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Composition of Vitamin Premix (DCH SYN VIT)                                   Ingredient            Amount                                                  ______________________________________                                        Vitamin A (Rovimix, 650,000 IU/g)                                                                   500.0 mg                                                Vitamin D.sub.3 (1,000,000 IU/g)                                                                    12.0 mg                                                 Vitamin E (Eastman 700 IU/g)                                                                        714.0 mg                                                2-Methyl-1,4-naphthoquinone                                                                         20.0 mg                                                 Thiamine.HCl          200.0 mg                                                Riboflavin            320.0 mg                                                d-Calcium pantothenate                                                                              400.0 mg                                                Niacin                1200.0 mg                                               Vitamin B.sub.12 (0.1% in mannitol)                                                                 800.0 mg                                                Biotin                4.0 mg                                                  Pyridoxine.HCl        120.0 mg                                                Folic acid            80.0 mg                                                 p-Aminobenzoic acid   2000.0 mg                                               Glucose               193.63 g                                                ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Effect of the Compound of EXAMPLE III                                         (R = isobutyl, R.sup.1 = ethyl) on Chick                                      Growth and Feed Efficiency                                                                                       Feed                                                    Level of  Chick       Conversion                                              Treatment Weight.sup.c                                                                              (g feed/                                   Diet.sup.a   (mg/kg).sup.b                                                                           (g ± std. dev.)                                                                        g gain)                                    ______________________________________                                        Untreated control                                                                           0        318.3 ± 41.9.sup.                                                                      1.15                                       Untreated Control                                                                          55        354.6 ± 45.6.sup.d                                                                     1.15                                       plus Penicillin G                                                             (as sodium salt)                                                              Untreated control                                                                          55        321.3 ± 41.3.sup.                                                                      1.13                                       plus Compound I                                                               (R = isobutyl, R.sup.1 =                                                      ethyl)                                                                        Untreated control                                                                          220       335.2 ± 31.6.sup.e                                                                     1.12                                       plus Compound I                                                               (R = isobutyl,                                                                R.sup.1 = ethyl)                                                              ______________________________________                                         .sup.a All diets based on Untreated Control Diet. Diets stored at             4° C. Treatments were premixed with, and added at the expense of,      the rest of the dietary components.                                           .sup.b Expressed as active ingredient.                                        .sup.c At 15 days old. The last 13 days were on treatment. The chicks wer     Marek's vaccinated, White Mountain X Hubbard cockerels. Average initial       weight was 51.4 g.                                                            .sup.d Growth enhanced compared with untreated controls (p < 0.05).           .sup.e Growth enhanced compared with untreated controls (p is                 approximately 0.053).                                                    

The invention has been described in detail with particular reference topreferred embodiments thereof, but it will be understood that variationsand modifications can be effected within the spirit and scope of theinvention.

We claim:
 1. A method for increasing the efficiency of feed utilizationby animals which comprises administering to said animals an effectivefeed utilization efficiency increasing amount of a compound of theformula ##STR4## wherein each R is independently, an alkyl group of 1 to6 carbon atoms and each R¹ is, independently, an alkyl group of 1-6carbons or hydrogen,or the physiologically acceptable salts thereof. 2.The method of claim 1 wherein said animals are meat-producing,egg-producing or milk-producing animals.
 3. The method of claim 1wherein said animals are poultry.
 4. The method of claim 1 wherein saidanimals are chickens.
 5. The method of claim 1 wherein each R is analkyl group of 3-5 carbons and each R¹ is an alkyl group of 1-3 carbons.6. The method of claim 1 wherein each R is isobutyl and each R¹ isethyl.
 7. The method of claim 1 wherein said effective amount is about 2to about 100 mg per kg of body weight per day.
 8. The method of claim 1wherein said effective amount is about 5 to about 50 mg per kg of bodyweight per day.
 9. A method for promoting the growth of meat-producinganimals comprising administering to said animals an effective growthpromoting amount of a compound of the formula ##STR5## wherein each R isindependently, an alkyl group of 1 of 6 carbon atoms and each R¹ is,independently, an alkyl group of 1-6 carbons or hydrogen,or thephysiologically acceptable salts thereof.
 10. The method of claim 9wherein said animals are nonruminant animals.
 11. The method of claim 9wherein said animals are poultry.
 12. The method of claim 9 wherein saidanimals are chickens.
 13. The method of claim 9 wherein each R is analkyl group of 3-5 carbons and each R¹ is an alkyl group of 1-3 carbons.14. The method of claim 9 wherein each R is isobutyl and each R¹ isethyl.
 15. The method of claim 9 wherein said effective amount is about2 to about 100 mg per kg of body weight per day.
 16. The method of claim9 wherein said effective amount is about 5 to about 50 mg per kg of bodyweight per day.